Transplantation & Cellular Therapy, M.D. Anderson Cancer. Center, Houston, TX; 2 University of Texas M.D. Anderson. Cancer Center, Houston, TX; 3 Stem Cell ...
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Abstracts / Biol Blood Marrow Transplant 20 (2014) S257eS285
aGVHD, it was 6.5 infections/1000 person-days (p-value¼0.022). These data support the hypothesis that gut aGVHD predisposes patients to development of EB-BSI, given the asymmetric distribution of EB-BSI after onset of aGVHD. We plan to analyze the infection densities in several other groups and risk factors associated with higher infection density in patients with gut aGVHD specifically. To our knowledge, this is the first study to demonstrate that the development of gut aGVHD increases the risk for EB-BSI. Strategies to reduce the elevated risk of EB-BSI in patients who develop gut aGVHD, such as prophylactic use of probiotics, should be considered based on these findings.
depositions are found in the squamous epithelium and dermis, blood vessels and damaged sweat glands. In the lip biopsy of GVHD patients, C3 depositions are found in the lesions associated with gland damage and regeneration, and damaged blood vessels. In summary, we conclude that C3 mediates Th1/Th17 polarization in human T cell activation and skin GVHD in patients. Studies on complement system and GVHD will not only significantly advance our knowledge of GVHD but also provide a rationale for using complement inhibitors as novel therapeutic interventions for GVHD.
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Early T-Cell Chimerism Is Valuable in Predicting Early Mortality from Steroid-Resistant Acute Graft Versus Host Disease after Myeloablative Allogeneic Haematopoietic Cell Transplantation Lia Minculescu 1, Hans Ole Madsen 2, Henrik Sengelov 3. 1 Clinical Immunology, National University Hospital, Copenhagen, Denmark; 2 Clinical Immunology, National University Hospital, Copemhagen, Denmark; 3 Department of Hematology L, National University Hospital, Rigshospitalet, Copenhagen, Denmark
Complement Component C3 Mediates Th1/Th17 Polarization in Human T Cell Activation and Cutaneous Graft-Versus-Host Disease Qing Ma 1, Dan Li 2, Amin M. Alousi 3, Richard E. Champlin 4, George E. Sale 5, Vahid Afshar-Kharghan 2. 1 Stem Cell Transplantation & Cellular Therapy, M.D. Anderson Cancer Center, Houston, TX; 2 University of Texas M.D. Anderson Cancer Center, Houston, TX; 3 Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX; 4 Stem Cell Transplantation & Cellular Therapy, UT MD Anderson Cancer Center, Houston, TX; 5 Fred Hutchinson Cancer Rsrch Univ Wash, Seattle, WA Graft-verses-host disease (GVHD) is a major complication in allogeneic bone marrow transplantation (allo-HSCT), and characterized by epithelial cell injury in skin, intestine and liver. The development of GVHD involves donor T cell activation including proliferation, differentiation and inflammatory cytokine production, which lead to specific tissue damage. The interactions between the complement system and lymphocytes have been shown to regulate alloreactive T cell and APC function in the setting of allograft rejection. There are three pathways that activate the complement system: the alternative, lectin and classical pathways; all of which converge on the formation of the C3 convertase to propagate the complement cascade. Recently, we reported that mice deficient in the central component of complement system C3 had significantly lower GVHD-related mortality/ morbidity and C3 modulated Th1/Th17 polarization in mouse GVHD. Given the emerging role of complement in alloimmune responses and T cell activation in animal models, it is important to address whether C3 modulates human T cell activation, polarization, expansion and differentiation. Compstatin is a 13-residue cyclic peptide that specifically binds to human C3 and inhibits complement activation, thus a favorable precursor peptide for the development of an anticomplement drug for oral use. Herein, we investigate the functional consequences of blocking C3 activation on human T cell activation. The production of IFN-g (Th1), IL-4 (Th2), IL17 (Th17), IL-2 and TNF-a was determined simultaneously in normal donor samples to examine whether Compstatin affects T cell activation and polarization in vitro. We found that blocking C3 activation with Compstatin significantly inhibits Th1/Th17 polarization in activated human CD4+ T cells. The production of IL-2 and TNF-a are reduced in CD4+ but not in CD8+ T cells. Moreover, Compstatin treatment significantly decreases the proliferation of both CD4+ and CD8 +T cells stimulated with OKT3 plus CD28 or allogeneic DCs in MLR. It has been reported that patients with sclerotic-type chronic GVHD (ScGVHD) have significantly elevated C3 in the serum. We examined the degree of C3 deposition in the skin and lip samples retrieved from our GVHD tissue repository of human allo-HSCT recipients. In the skin GVHD tissues, C3
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The aim of this study was to evaluate the impact of early chimerism status on incidence and clinical course of acute GVHD in allogeneic transplant recipients. From March 2008 to February 2013, 106 eligible patients were included in the study. Median patient age was 40 (16-58) years with 66 (62%) males and 40 (38%) females. Pre-transplant diagnoses were AML (44 patients, 42%), ALL (29 patients, 27%), MDS (17 patients, 16%), CML (8 patients, 8%), NHL (2 patients, 2%) and other (6 patients, 6%). Donors were HLA-identical siblings in 33 (31%) patients and matched unrelated donors in 73 (69%) patients. Stem cell sources were bone marrow (61 patients, 58%) and peripheral blood (45 patients, 42 %). Patients were conditioned with Cyclophosphamide and TBI 12 Gy (63 patients, 59%), VP16 and TBI 12 Gy (31 patients, 29%), Cyclophosphamide and Busulfan (10 patients, 9%), moreover 1 patients received Busulfan and Melphalan and another patient Busulfan and VP16. T-cell line specific chimerism was analysed by PCR-VNTR and chimerism samples were measured on day 35. Donor chimerism (DC) was defined as 95% or more cells of donor origin within CD4 and CD8 T-cells and mixed chimerism (MC) as less than 95% donor CD4 and CD8 T-cells. At a followup time of 767 (140-1940) days 71 (67%) patients were still alive. Among deceased patients, cause of death was TRM in 23 (66%) patients and relapse in 12 (34%) patients. Acute GVHD occurred in 68 (64%) patients with 49 (46%) patients diagnosed with grade II-IV aGVHD. The incidence and grade of aGVHD was not different in DC versus MC patients. Early survival probability at day 180 estimated by Kaplan-Meier showed significantly better outcome for patients with MC compared to DC (p¼0.04). Death from TRM with relapse as competing risk analysed with cumulative incidence emphasized poorer outcome for MC patients compared to DC patients (p¼0.03).We then analysed the clinical course in MC and DC patients diagnosed with aGVHD grade II-IV who later on died from TRM. Of these 21 patients, 12/14 DC patients compared to 1/7 MC were under treatment with either high dose Prednisolone ( 1.5 mg/kg body weight) or Infliximab by their time of death (p¼0.007, figure 1), associating early Tcell DC with steroid-resistant aGVHD. This suggest, that even though the incidence and grade of aGVHD were not different between patients with DC versus MC, the clinical course of aGVHD seem to differ significantly in the two groups with higher mortality from steroid-resistant aGVHD in DC
